Iowa Institute of Oral Health Research, University of Iowa College of Dentistry, Iowa City, IA, USA.
Periodontics, University of Iowa College of Dentistry, Iowa City, IA, USA.
J Dent Res. 2023 Jan;102(1):103-115. doi: 10.1177/00220345221123256. Epub 2022 Oct 24.
Recent genome-wide association studies have suggested novel risk loci associated with periodontitis, which is initiated by dysbiosis in subgingival plaque and leads to destruction of teeth-supporting structures. One such genetic locus was the tumor necrosis factor receptor-associated factor 3 interacting protein 2 (), a gene encoding the gate-keeping interleukin (IL)-17 receptor adaptor. In this study, we first determined that carriers of the lead exonic variant rs13190932 within the locus combined with a high plaque microbial burden was associated with more severe periodontitis than noncarriers. We then demonstrated that TRAF3IP2 is essential in the IL-17-mediated CCL2 and IL-8 chemokine production in primary gingival epithelial cells. Further analysis suggested that rs13190932 may serve a surrogate variant for a genuine loss-of-function variant rs33980500 within the same gene. null mice () were more susceptible than wild-type (WT) mice to the -induced periodontal alveolar bone loss. Such bone loss was associated with a delayed clearance and an attenuated neutrophil recruitment in the gingiva of mice. Transcriptomic data showed decreased expression of antimicrobial genes, including , , and , in the mouse gingiva in comparison to WT mice prior to or upon oral challenge. Further 16S ribosomal RNA sequencing analysis identified a distinct microbial community in the mouse oral plaque, which was featured by a reduced microbial diversity and an overabundance of genus bacteria. More was observed in the mouse gingiva than WT control animals in a ligature-promoted invasion model. In agreement, neutrophil depletion resulted in more local gingival tissue invasion by . Thus, we identified a homeostatic IL-17-TRAF3IP2-neutrophil axis underpinning host defense against a keystone periodontal pathogen.
最近的全基因组关联研究表明，与牙周炎相关的新的风险位点，牙周炎是由龈下菌斑的失调引起的，导致牙齿支持结构的破坏。其中一个遗传位点是肿瘤坏死因子受体相关因子 3 相互作用蛋白 2 ()，它是编码门控白细胞介素 (IL)-17 受体衔接子的基因。在这项研究中，我们首先确定了 基因内的先导外显子变异 rs13190932 的携带者与非携带者相比，携带该基因的个体与高菌斑微生物负荷相结合，与更严重的牙周炎有关。然后，我们证明了 TRAF3IP2 在 IL-17 介导的 CCL2 和 IL-8 趋化因子在原代牙龈上皮细胞中的产生中是必不可少的。进一步的分析表明，rs13190932 可能是同一基因内真正的功能缺失变异 rs33980500 的替代变体。 缺失小鼠 ()比野生型 (WT) 小鼠更容易受到 诱导的牙周牙槽骨丢失。这种骨丢失与 缺失小鼠牙龈中 的清除延迟和中性粒细胞募集减少有关。转录组数据显示，与 WT 小鼠相比， 缺失小鼠在口腔挑战前或口腔挑战后，抗菌基因如 、 、和 的表达减少。进一步的 16S 核糖体 RNA 测序分析确定了 缺失小鼠口腔斑块中的独特微生物群落，其特征是微生物多样性降低和 属细菌过度生长。与 WT 对照动物相比，在结扎促进的 侵袭模型中观察到更多的 。同样，中性粒细胞耗竭导致更多的局部牙龈组织被 侵袭。因此，我们确定了一个维持性的 IL-17-TRAF3IP2-中性粒细胞轴，为宿主防御关键牙周病原体提供了基础。
